Disruption of SMIM1 causes the Vel− blood type

Abstract

Here, we report the biochemical and genetic basis of the Vel blood group antigen, which has been a vexing mystery for decades, especially as anti-Vel regularly causes severe haemolytic transfusion reactions. The protein carrying the Vel blood group antigen was biochemically purified from red blood cell membranes. Mass spectrometry-based de novo peptide sequencing identified this protein to be small integral membrane protein 1 (SMIM1), a previously uncharacterized single-pass membrane protein. Expression of SMIM1 cDNA in Vel− cultured cells generated anti-Vel cell surface reactivity, confirming that SMIM1 encoded the Vel blood group antigen. A cohort of 70 Vel− individuals was found to be uniformly homozygous for a 17 nucleotide deletion in the coding sequence of SMIM1. The genetic homogeneity of the Vel− blood type, likely having a common origin, facilitated the development of two highly specific DNA-based tests for rapid Vel genotyping, which can be easily integrated into blood group genotyping platforms. These results answer a 60-year-old riddle and provide tools of immediate assistance to all clinicians involved in the care of Vel− patients.

Erythrogene: a database for in-depth analysis of the extensive variation in 36 blood group systems in the 1000 Genomes Project

“…Nine of the 53 non-Alu SVs were found in the GYPA and GYPB genes, known to have a high rate of recombination and gene conversions. However, we noted that neither the 37-bp insertion characteristic of the RHD pseudogene 31 nor the 17-bp deletion in SMIM1 underlying the Vel-negative phenotype [32][33][34] were called in 1000G. While the former allele was still detected because of a downstream stop codon (p.Tyr269Ter), the latter remained invisible.…”

Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization

“…Encouraged by our recent success in elucidating the molecular bases of 3 other long-sought-after blood group antigens, [6][7][8] we decided to reinvestigate the case of this French woman.…”

Molecular Screening for Vel- Blood Donors in Southwestern Germany

“…In 2013 different groups reported the genetic basis of the Vel- blood type [4,5,6]. A 17 bp frame-shift deletion (64-80del) in the coding region of the SMIM1 gene was homozygous in all Vel- samples.…”

“…A 17 bp frame-shift deletion (64-80del) in the coding region of the SMIM1 gene was homozygous in all Vel- samples. The reduced or weak expression of the Vel antigen was associated with a heterozygous 64-80del genotype [4,5]. The International Society of Blood Transfusion (ISBT) Working Party for Red Cell Immunogenetics and Blood Group Terminology assigned the blood group system name VEL and number 034 and promoted Vel from a genetically unresolved blood group antigen (ISBT number 212001) to the new system defined by the SMIM1 locus (antigen number 034001).…”